Functionalized erythrocyte-derived optical nanoparticles to target ephrin-B2 ligands

Abstract

Over-or under-expression of erythropoietin-production human hepatocellular receptors (Eph) and their ligands are associated with various diseases. Therefore, these molecular biomarkers can potentially be used as binding targets for the delivery of therapeutic and/or imaging agents to cells characterized by such irregular expressions. We have engineered nanoparticles derived from erythrocytes and doped with the near-infrared (NIR) FDA-approved dye, indocyanine green. We refer to these nanoparticles as NIR erythrocyte-derived transducers (NETs). We functionalized the NETs with the ligand-binding domain of a particular Eph receptor, EphB1, to target the genetically modified human dermal microvascular endothelial cells (hDMVECs) with coexpression of EphB1 receptor and its ligand ephrin-B2. This cell model mimics the pathological phenotypes of lesional endothelial cells (ECs) in port wine stains (PWSs). Our quantitative fluorescence imaging results demonstrate that such functionalized NETs bind to the ephrin-B2 ligands on these hDMVECs in a dose-dependent manner that varies sigmoidally with the number density of the particles. These nanoparticles may potentially serve as agents to target PWS lesional ECs and other diseases characterized with over-expression of Eph receptors or their associated ligands to mediate phototherapy.

Near Infrared Fluorescence Imaging of Intraperitoneal Ovarian Tumors in Mice Using Erythrocyte-Derived Optical Nanoparticles and Spatially-Modulated Illumination

“…In both panels, * and ** indicate p < 0.05, and p < 0.01, respectively. nRBCs-ICG are also amenable to surface functionalization with various biomolecules including folate, and antibodies (e.g., anti-HER2) [40,54,55]. Given the significance of molecular profiling for development of targeted therapeutics [56], nRBCs-ICG can be functionalized with personalized targeting moieties to enhance specificity towards cancerous ovarian cells.…”

Nucleic Acid Delivery with Red-Blood-Cell-Based Carriers

“…Due to the similar size, it can be assumed that nano-erythrosomes too, despite the stiffness of the membrane due to the presence of cholesterol, can take advantage of similar pathways. So far, even if in presence of precise hints on the internalization of nanoerythrosomes by cancer cells and endothelial cells [ 192 , 218 ], the mechanism is still unclear.…”

“…Antibody conjugation has also been exploited for nano-erythrosomes. While loaded with indocyanine green for near-infrared fluorescence imaging, they are conjugated with anti-HER2 (human epidermal growth receptor) antibodies via DSPE-PEG-NH 2 (2000 Da in molecular weight), to achieve better in vivo imaging properties [ 192 ]; also, they have been functionalized with ephrin-B1 ligand receptor, to actively target human dermal microvascular endothelial cells [ 218 ].…”

Harnessing the Power of Eph/ephrin Biosemiotics for Theranostic Applications

“…Eph-targeted nanoparticle formulations can also be the basis for advanced theranostic applications. For example, erythrocyte-derived nanoparticles were targeted to ephrin-B2 ligands via functionalization with the ligand binding domain of EphB1 [160]. Inclusion of a NIR-active dye (near infrared) in the nanoformulation makes them a promising platform for long wavelength phototherapies targeted to diseased cell populations.…”